Essential role for G proteins in prostate cancer cell growth and signaling

Purpose: G proteins are involved in the regulation of multiple cellular fun ctions, including metabolism and proliferation. We studied the role of Gi/o protein subunits in the growth and survival of prostate cancer cells. Materials and Methods: We investigated the effects of pertussis toxin and t he G beta gamma sequestrant peptide G protein coupled receptor kinase 2 car boxy terminus on the growth and mitogenic signaling of prostate cells. Results: Pertussis toxin treatment inhibited the lysophosphatidic acid and serum mediated growth of prostate cancer PC-3 cells by 70% to 80% but showe d no effect on insulin-like growth factor 1 (IGF-1) or epidermal growth-fac tor (EGF) mediated growth of these cells. Growth and survival of cells are dependent on activation of intracellular signaling cascades, including thes e of the mitogen activated protein kinase and Akt pathways. Treatment of th e PC-3 cells with lysophosphatidic acid, EGF or serum induced an 8-fold inc rease in the phosphorylation levels of the mitogen activated protein kinase s Erk 1 and 2, and a 3-fold increase in the phosphorylation level of Akt. E rk 1/2 and Akt phosphorylation by lysophosphatidic acid and serum was inhib ited by pertussis toxin, suggesting a Gi/o subunit dependent mechanism. EGF and IGF-1 mediated increase in phosphorylation of Erk 1/2 and Akt was inde pendent of pertussis toxin action. Expression of the G beta gamma sequestra nt peptide G protein coupled receptor kinase 2 carboxy terminus inhibited t he lysophosphatidic acid and serum mediated activation of Erk 1/2 and Akt b ut showed no effect on the IGF-1 or EGF mediated response. Finally, we show ed that activation of the Erk 1/2 pathway in the prostate cancer cells by l ysophosphatidic acid and serum is dependent on the EGF receptor and c-Src p rotein tyrosine kinases. Whereas activation of Akt by these stimuli is not dependent on protein tyrosine kinase activation, it is mediated by PI3K. Conclusions: These data indicate that lysophosphatidic acid and serum induc e proliferation and mitogenic signaling of prostate cancer cells. Important ly, the serum mediated growth of these cells is dependent on Gi beta gamma subunits, suggesting an important regulatory role for G proteins in the gro wth of prostate cancer cells.